IRAK2 deficiency causes immune dysregulation through defective Myddosome assembly and enhanced interferon responses

Interleukin-1 receptor-associated kinase 2 (IRAK2) is essential for the Myddosome complex formation downstream of Toll-like receptors. We identify twelve patients with a homozygous loss-of-function copy number variant in IRAK2, designated IRAK2-∆ex2. Most patients present with recurrent infections, autoantibody production, and gastrointestinal ulceration. Two patients were clinically diagnosed with primary immunodeficiency, while the majority fulfill diagnostic criteria for autoimmune or autoinflammatory diseases. The IRAK2-∆ex2 protein fails to interact with IRAK4, leading to impaired activation of nuclear factor kappa B signaling via the Myddosome complex. An elevated type I interferon signature is observed in the patients, which is confirmed in bone marrow-derived macrophages from knock-in mice and knockout cell lines. Mechanistically, our data are consistent with engagement of a TRIF-dependent interferon pathway. Baricitinib attenuates the elevated interferon signature in patient-derived cells ex vivo and cell lines. Here, we show IRAK2 deficiency as a monogenic immune dysregulation disorder. Interleukin-1 receptor-associated kinase 2 (IRAK2) is essential for Myddosome complex formation downstream of most Toll-like receptors. Here, the authors show a loss-of-function copy number variant of IRAK2 associated with immunodeficiency, autoimmunity, and autoinflammation, which disrupts IRAK2 interaction with IRAK4 and further downstream Myddosome formation, accompanied by enhanced interferon responses.

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Publication Details

Journal
Nature Communications
Published
2026-05-21
DOI
https://doi.org/10.1038/s41467-026-73383-8
Primary Topic
Immune Response and Inflammation
Type
article
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article

IRAK2 deficiency causes immune dysregulation through defective Myddosome assembly and enhanced interferon responses

S Wang, Chengshun Chen, Jing Xue, C Liu et al.
Nature Communications
Immune Response and Inflammation
article

IRAK2 deficiency causes immune dysregulation through defective Myddosome assembly and enhanced interferon responses

S Wang, Chengshun Chen, Jing Xue, C Liu, Yusha Wang, Z.H. Liu, Jinjian Fu, Hua Zhong, Ying Jin, Xiangwei Sun, Q Zhou, Yuhao Yao, Xia Gao, Yi-Xiang Wang, Li Guo, Lihong Wen, J Yang, T Y He, J Li, Xu Han, Zhijuan Kang, Yi Liu, Jiahui Zhang, Hongmei Zhao, Meiping Lu, Yudie Fei, Shuangyue Ma, Xiang Chen, Xiaomin Yu, Changming Zhang, Liang Zhang, Lin Liu
article en

Abstract

Interleukin-1 receptor-associated kinase 2 (IRAK2) is essential for the Myddosome complex formation downstream of Toll-like receptors. We identify twelve patients with a homozygous loss-of-function copy number variant in IRAK2, designated IRAK2-∆ex2. Most patients present with recurrent infections, autoantibody production, and gastrointestinal ulceration. Two patients were clinically diagnosed with primary immunodeficiency, while the majority fulfill diagnostic criteria for autoimmune or autoinflammatory diseases. The IRAK2-∆ex2 protein fails to interact with IRAK4, leading to impaired activation of nuclear factor kappa B signaling via the Myddosome complex. An elevated type I interferon signature is observed in the patients, which is confirmed in bone marrow-derived macrophages from knock-in mice and knockout cell lines. Mechanistically, our data are consistent with engagement of a TRIF-dependent interferon pathway. Baricitinib attenuates the elevated interferon signature in patient-derived cells ex vivo and cell lines. Here, we show IRAK2 deficiency as a monogenic immune dysregulation disorder. Interleukin-1 receptor-associated kinase 2 (IRAK2) is essential for Myddosome complex formation downstream of most Toll-like receptors. Here, the authors show a loss-of-function copy number variant of IRAK2 associated with immunodeficiency, autoimmunity, and autoinflammation, which disrupts IRAK2 interaction with IRAK4 and further downstream Myddosome formation, accompanied by enhanced interferon responses.

Nature Communications
Central South University (CN), Army Medical University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Sichuan University (CN), Nanjing General Hospital of Nanjing Military Command (CN), Sir Run Run Shaw Hospital (CN), West China Hospital of Sichuan University (CN), Children's Hospital of Zhejiang University (CN), Zhoushan Hospital (CN), Zhejiang Provincial People's Hospital (CN), Hunan Children's Hospital (CN), Shenzhen Children's Hospital (CN), Second Affiliated Hospital of Zhejiang University (CN), Hangzhou Medical College (CN), Zhejiang University (CN), Nanjing Medical University (CN), Nanjing University (CN), University of South China (CN)
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Immune Response and Inflammation
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